# The role of lamin B1 in normal and myelodysplastic hematopoiesis

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2024 · $555,935

## Abstract

ABSTRACT
Hematopoietic stem cells (HSCs) maintain life-long blood production and acquire somatic mutations leading to
premalignant clonal expansion and myelodysplastic syndromes (MDS). Eukaryotic genomes are hierarchically
organized at distinct spatial levels. However, it is largely unclear how this higher order three-dimensional (3D)
genome organization orchestrates coordinate regulation of gene expression underlying developmental fate
decisions. Nuclear lamins are structural proteins that establish genome architecture and play a prominent role
in stem cells and disease. Lamin B1 is the most abundant nuclear lamin in hematopoietic cells, and its expression
is broadly decreased in aging and due to recurrent 5q deletions in MDS. However, we lack a fundamental
understanding of how lamin B1 regulates genome organization, how this 3D organization impacts HSC fate
decisions, and whether 5q deletion of LMNB1 contributes to MDS pathogenesis and progression.
Here, we propose to systematically answer these outstanding questions to gain a fundamental understanding of
how lamin B1 contributes to normal and MDS hematopoiesis. Our team consists of a stem cell biologist with
expertise in hematologic disease modeling (Doulatov), a molecular biologist with expertise in 3D genomes
(Duan), computational biologist with expertise in 3D genomes (Noble), and a biochemist with expertise in
chromatin regulation (Escobar). In preliminary studies, we examined the molecular and functional consequences
of lamin B1 loss on human hematopoiesis. These experiments revealed that lamin B1 loss alters chromatin
organization and nuclear morphology and promotes HSC and myeloid cell fates at the expense of lymphopoiesis.
We propose to build on these preliminary studies as follows: Aim 1, Determine the role of lamin B1 and LBR in
human HSC function and clonal dynamics in vivo; Aim 2, Define how lamin B1 regulates chromatin architecture
and gene expression to control HSC fate; Aim 3, Determine whether 5q deletion of LMNB1 underlies impaired
hematopoiesis in del5q MDS. The significance of these studies is that they will elucidate how lamin-dependent
3D genome regulates HSC fate. The health relevance is that the proposed work may identify lamin B1 as a
tumor suppressor in del5q MDS. Since 5q deletion is often associated with high-risk MDS, these studies will help
identify a major genetic driver and explore therapeutic vulnerabilities for this disorder.

## Key facts

- **NIH application ID:** 10854845
- **Project number:** 5R01HL169156-02
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Sergei Doulatov
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $555,935
- **Award type:** 5
- **Project period:** 2023-07-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10854845

## Citation

> US National Institutes of Health, RePORTER application 10854845, The role of lamin B1 in normal and myelodysplastic hematopoiesis (5R01HL169156-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10854845. Licensed CC0.

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